Fluoropolymer Barrier Materials For Containers

ABSTRACT

A container having a barrier layer is provided. The container may be of thermoplastic and the barrier may inhibit materials from leaching from the thermoplastic material or from extraction of compounds from medicants by the thermoplastic. A process is also described that allows for molding thin barrier layers as container lines and for forming thermoplastic containers with barrier liners.

BACKGROUND OF THE INVENTION

Syringes used for delivery of medicaments are principally constructed ofa barrel and a stopper. The stopper is slidably fitted within thesyringe barrel and may have a stopper rod affixed to it for actuation ofthe syringe and delivery of medicament. The stopper is generallyconstructed of an elastomer, with silicone oil applied. The silicone oilis applied to reduce sliding friction between the stopper and barrel andto improve the seal between them. The oil allows for ease of slidingwhen administering a dose which may ensure the full dose can beadministered. Partial dosing is of particular concern in the case ofpens and so-called auto injecting syringes. In such applications, theoil is also critical to prevent jamming of the device which can lead totrauma at the site of injection. The improved sealing provided bysilicone oil also may ensure that no foreign contaminants like bacteriaenter the syringe.

Recently there has developed a trend favoring pre-filled syringes whichfunction to both store and deliver medicaments. Such pre-filled syringesmay offer cost savings to the pharmaceutical industry and may improvesafety, convenience and efficacy of medicament delivery.Biopharmaceuticals are an important class of pharmaceuticals that mayincrease the use of pre-filled syringes and related devices (pens, autoinjectors and the like). Such biopharmaceuticals may include insulin,vaccines, antibodies, blood products, hormones, cytokines, and the like.As more pharmaceuticals and particularly biopharmaceuticals utilizedelivery in pre-filled syringe and similar devices, the challenges ofconventional syringe technology become apparent.

Several aspects of traditional syringe construction present a challengefor their use as pre-filled syringes. The use of silicone oil is aconcern, because the oil may degrade the medicament and because a smallamount of silicone may be injected with it. The oil may also be ofparticular concern with regard to biopharmaceuticals because it maycause aggregation of certain proteins.

Another issue that arises in prefilled syringes is that the elastomer ofthe stopper may contain leachable and extractable contaminants. Thesemay also contaminate the medicament upon long term storage in syringes.Trace amounts of residual monomer or plasticizer or other impuritiesfrom the stopper can adversely effect the therapeutic or can have anadverse impact on the patient once injected.

Among the many other considerations affecting prefilled syringe devicesand similar devices and their components are the need to be sterilized,stability with transport and storage for up to a few years, opticalclarity, the need to integrate into existing filling equipment(including the durability requirements for stopper cleaning andinsertion into the syringe barrel), leachables and extractables of allcomponents of the syringe, and the need to maintain sterility fromfilling through administering of the contents, and finally userpreferences and ergonomic considerations. For a variety of reasons theprefilled syringe market uses both glass and plastic barrels.

The foregoing considerations apply in similar manner to othercontainers, particularly containers suitable for medicaments. Forexample, rigid tip caps and other container closures as well as syringebarrels may benefit from barrier materials. In some such applications,the improved barrier material may serve as a barrier between the productcontained in the container and the environment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of the thermoforming equipment usedto make the barrier film preform of Example 2.

FIG. 2A depicts the 4-cavity mold that was used in the thermoformingequipment of FIG. 1.

FIG. 2B depicts the side view of the 4-cavity mold that was used in thethermoforming equipment of FIG. 1.

FIG. 3 is a representative drawing of the lay-up in the press forcompression molding.

FIG. 4 is a depicts a side view of the cavity used to make the stopperin Example 7.

FIG. 5 depicts a cross sectional view of a syringe stopper according toone embodiment of the invention.

FIG. 6 depicts a cross sectional view of a syringe stopper according toanother embodiment of the invention.

FIG. 7 depicts a cross sectional view of a syringe stopper according toyet another embodiment of the invention.

FIG. 8 depicts a cross-sectional view of a syringe stopper according toa further embodiment of the invention.

FIG. 9 depicts a cross-sectional view of a syringe stopper according toan embodiment of the invention.

FIG. 10A depicts a cross-sectional view of a syringe stopper accordingto an embodiment of the invention.

FIG. 10B depicts a cross-sectional view of a syringe stopper accordingto another embodiment of the invention.

FIG. 11 depicts a cross-sectional view of a syringe stopper according toyet another embodiment of the invention.

FIG. 12 depicts a cross-sectional view of a syringe stopper according toa further embodiment of the invention.

FIG. 13 depicts a cross-sectional view of a syringe stopper according toan embodiment of the invention.

FIG. 14 is a schematic illustration of a cross-sectional view of thetest apparatus for accessing the barrier properties of a stopper.

FIG. 15 is a schematic illustration of a cross-sectional view of a testapparatus to determine the durability of a stopper to the vent tubeinstallation test.

FIG. 16 is a scanning electron micrograph (SEM) image showing across-section of a syringe stopper according to an embodiment of theinvention.

FIG. 17A is a schematic illustration of a portion of the containerformed in Example 11;

FIG. 17B is a schematic illustration of a cross-sectional view of thecontainer formed in Example 11.

FIG. 18A is a cross-sectional view of a vial stopper having a barrierlayer according to an embodiment of the invention.

FIG. 18B is a top view of a vial stopper having a barrier layeraccording to an embodiment.

DESCRIPTION OF THE INVENTION

The present invention provides a syringe stopper that is suitable foruse in syringes without silicone oil or other liquid lubricants. In oneaspect, the invention provides a low friction barrier between anelastomeric stopper material and a therapeutic in the syringe. Thebarrier may inhibit materials from leaching from the elastomer materialor from extraction of compounds from medicants by the elastomer. Aprocess is also described that allows for molding thin barrier layerswhile allowing adequate bonding with the elastomer.

In another aspect, the inventive barrier material may also be used onnon-elastomeric materials such as plastics (polypropylene,polycarbonate, polyethylene, etc) thermoplastics, specificallyfluoroplastic materials such EFEP, PVDF, PFA etc.

In certain embodiments, the invention may use barrier films includingexpanded fluoropolymer films and, particularly expandedpolytetrafluoroethylene films. Barrier films based on expanded PTFE canprovide for thin and strong barrier layers to leachables andextractables. The superior strength of the expanded fluoropolymerstructure allows these materials to form thin barriers which remainintact during the forming process and installation of the stopper intothe syringe body.

The use of at least partially porous and advantageously fibrilizingmaterials, such as ePTFE in combination with barrier materials mayprovide many advantages. In one aspect, the use of such partially porousmaterials may provide a scaffold that enables thin strong barrier layersto be made and improves the bond between the elastomer and the barrier.Barrier compliance is critical to maintaining a seal between the stopperand the barrel; porous materials may also provide for improvedcompliance of the stopper. Improved compliance may result from reducedfilm thickness, flexural compliance, or the compressibility of one ormore layers of the porous material. Accordingly, by providing a barrierthat is at least partially porous to the outside of the syringe stopper,the seal between the stopper and syringe barrel may be improved whilethe sliding force is minimized.

The barriers may be of single layer or multiple layer construction. Asdescribed herein, layers may be described functionally. However, thefunctional names of the various layers in the descriptions ofembodiments that follow may not describe all of the potential functionsof any given layer. Accordingly, it will be understood that suchfunctional nomenclature is not intended to be limiting of any layerproperty. For example, a barrier layer may have additional propertiesand functions such as providing a low friction surface, increasing bondstrength and the like. Moreover, in multi-layer embodiments, each layermay contribute to the reduction of leachable and extractable materialsregardless of its designation as a barrier layer or otherwise.

FIG. 5 shows a first embodiment of syringe stopper of the currentinvention comprised of an elastomer body 10, and a fluoropolymer barrier20. The elastomer body 10 can be comprised of any elastomer suitable forthe application, most notably rubbers constructed butyl, bromobutyl,chlorobutyl, silicone, nitrile, styrene butadiene, polychloroprene,ethylene propylene diene, fluorelastomers, or blends of any of theforegoing. The materials of the barrier 20 are chosen to provide lowcoefficient of friction, compliance, low extractables and leachables,good barrier properties as they relate to extractables and leachablesfrom the elastomer body.

In an embodiment, the barrier (20) may comprise a single layer ofdensified ePTFE. FIG. 8 shows a syringe stopper of the current inventioncomprised of an elastomer body, 10, and a barrier layer, 30. Theelastomer body may comprise any of these previously mentioned materials.In this aspect, the barrier film may comprise densified expandedfluoropolymer, preferably densified ePTFE.

A densified ePTFE film may be obtained in the manner described in U.S.Pat. No. 7,521,010 to Kennedy, et al. The densified expanded PTFE filmis then combined with an elastomer to construct a syringe stopper. Inthis embodiment, the densified ePTFE film is thermoformed to make apreform. Thermoforming is done at process temperatures sufficientlyabove the nodal melt to ensure melt forming while preserving barrier andstrength properties. The high strength expanded film allows for formingextremely thin barrier films. Barrier films can be made with thicknessesranging from 0.5 micron to 20 microns. The films are preferentially lessthan 30 microns. The film can optionally be pre treated or post treatedwith chemical etching, plasma treating, corona, roughening or the liketo improve bonding to the elastomer body.

The thermoformed, densified ePTFE preform can be combined with theelastomer body by injection molding, compression molding, priming andpost laminating around an elastomer perform, or other suitable means.Examples of elastomers that can be used to form the elastomer bodyinclude silicone, butyl, nitrile, polyurethane, fluoroelastomers,styrene ethylene butadiene styrene elastomers, styrene butadienerubbers, and the like.

In another embodiment, the barrier 20 may comprise a compositefluoropolymer film having a barrier layer 30 and a porous layer 40. Thebarrier layer 30 can be comprised of densified ePTFE, PTFE, fluorinatedethylene propylene (FEP), polyethylene, polypropylene, polyvinylidenefluoride, polyvinylfluoride, perfluoropropylevinylether, perfluoroalkoxypolymers, and the like. The porous layer 40 can be comprised of ePTFE orother porous expanded and advantageously fibrilizing fluoropolymers (forexample, ePTFE as taught in U.S. Pat. No. 6,541,589). The ePTFE layersmay advantageously be filled with an organic or inorganic material toprovide color lubricity or other function.

In another embodiment a barrier is constructed by coating or otherwisedepositing a barrier polymer onto the porous expanded layer to create acomposite film. One such example of this would be to deposit granular orpowdered fluoropolymers such as powdered PTFE onto the porous ePTFEsurface in a coating process. The ePTFE support should be constructed tobe thermally stable enough to allow heat treatment of the depositedfluoropolymer for the creation of a barrier or for bonding of thedeposited layer to the porous ePTFE support.

In certain embodiments, elastomer material may advantageously penetratethe porous structure of the barrier. FIG. 6 shows a cross-section of astopper according to an embodiment depicting the syringe barrel wall,50, the barrier film, 30, the porous layer, 40, and the elastomer body,10. Specifically, this figure shows a region of partial penetration 41of the elastomer material into the porous structure, 40. Penetration ofthe elastomer material into the porous structure may improve the bondbetween elastomer and barrier.

FIG. 7 shows a cross-section of another embodiment of a syringe stopperaccording to the invention including the syringe barrel wall, 50, abarrier 41, and an elastomer body, 10. The barrier is comprised of abarrier layer, 30, and a porous layer, 40. In this embodiment, thebarrier layer comprises a coating deposited onto the porous layer 40.The barrier layer may comprise a polymer at least partially imbibed intothe porous layer 40, in a manner that creates a porous layer compositesection 99. This porous layer composite section 99 may improve bondingof the barrier polymer to the porous layer. The porous composite sectionmay also provide support for the barrier polymer to impart strength,toughness, compliance and stability which may be beneficial in both theforming process and in the application.

In an aspect, the barrier layer 30 may comprise an imbibed barrierpolymer applied in a manner that allows leaves certain sections theporous layer exposed on the surface. In this aspect the porous layer maybe sufficiently exposed to allow the exposed sections to come in contactwith the syringe wall, 50. In this aspect, the porous polymer isadvantageously comprised of ePTFE or other suitable lubricious, expandedporous fluoropolymer. The exposed sections of fluoropolymer may reducethe coefficient of friction of the barrier film against the wall.

In many of the embodiments of the invention, a porous layer is disposedbetween the barrier layer surface and the elastomer of the stopper. Theinventive stopper may advantageously include various degrees ofpenetration of either elastomer material or barrier polymer into theporous material as shown in FIGS. 9 through 13. FIG. 10A is across-sectional view of the stopper showing the elastomer layer (10) anda composite layer comprising a fluoropolymeric barrier layer (30) and aporous ePTFE layer (40). In this embodiment, the elastomeric materialfrom layer (10) substantially fills the pores of the ePTFE layer (40).

Alternatively, the barrier polymer (30) may substantially fill theporous structure (40), as in FIG. 11. In another aspect, the porousmaterial (40) is filled to a substantially similar degree with barrierpolymer (30) and elastomer (10), leaving few open pores in the porousstructure as in FIG. 10B. In still another aspect, both the barrierpolymer and the elastomer partially fill the porous structure, whileleaving some open pores between them as shown in FIG. 12. Othervariations of penetration of elastomer and or barrier fluoropolymer maybe readily apparent, one such variant shown in FIG. 13. Each may haveadvantages according to the specific application, with due considerationto the various desirable characteristics of the finished device, such asreduced friction, improved barrier properties, and improved sealing. Thedegree of penetration of either barrier polymer or elastomer may becontrolled by any means known, but include variations in time,temperature, pressure, and porosity of the porous material. In oneaspect the porous material may, for example have a porosity that varieswith depth.

In still another embodiment, the barrier may comprise a composite of adensified ePTFE film and a thin layer of porous ePTFE bonded to thebarrier layer film. A densified ePTFE film may be obtained as describedin U.S. Pat. No. 7,521,010 to Kennedy et al. The ePTFE/densified ePTFEcomposite may be combined in the manner described in U.S. Pat. No.6,030,694 to Dolan, et al.

In this embodiment, a composite barrier comprises a layer of densifiedePTFE film and a porous ePTFE layer. The porous ePTFE layer isconstructed in a manner that it retains most of its porosity throughthermoforming. It is also sufficiently compliant that it improvessealability against the syringe barrel wall. To accomplish this, atleast a portion of the porous layer may remain sufficiently open afterthermoforming and post compression molding with the elastomer. This openporosity allows some compressibility which may aid in the conformabilityand seal of the stopper to the surface.

The thickness of the densified ePTFE film would be suitably tailored tothe application with pre-thermoform thicknesses of less than 100microns, more preferably, less than 50 microns, more preferably lessthan 30 microns. Additionally, the flexural rigidity of the compositefilm would need to be suitably tailored to ensure compliance andsealability while retaining sufficient strength for this application.

The ePTFE porous layer would be preferably less than 150 microns thick.To improve performance as a bonding layer, the ePTFE porous layer shouldbe made sufficiently open to allow for at least partial penetration ofthe elastomer into the porous (i.e. and fibrillated structure onto thesurface of the nodes or fibrils) during elastomer forming.

To construct the barrier preform, the composite barrier may bethermoformed at temperatures, rates and pressures suitable to allow thedensified film to form to the shape of the female cavity of a stoppermold. The more porous ePTFE layer may be oriented toward the inside ofthe mold cavity, while the densified ePTFE barrier layer will beoriented toward the outer wall of the mold. The thermoforming can bedone at temperature ranges suitable to form the ePTFE based film,without fracturing or otherwise disturbing the barrier provided by thedensified ePTFE barrier layer. Suitable temperatures could be in therange of 330-400° C., more preferably 350-380° C. at pressures suitableto form without fracturing the barrier layer, or substantiallycollapsing the porous layer.

The thermoformed barrier preform may be integrated with an elastomericsyringe stopper of the current invention by, for example, by injectionmolding or compression molding an elastomer like butyl rubber orsilicone or Viton®. The porous ePTFE layer can be advantageously madestable to the elastomer injection or compression molding process,thereby maintaining some of its porous structure. The porous structuremay improve the bond of the elastomer to the barrier. This may result inimproved compliance for sealability, as the porous layer allows for somecompressibility for better, low force sealing.

In yet another embodiment, a barrier can be made by forming a thindensified composite comprising a porous ePTFE layer and a thermoplasticbarrier layer. In this aspect, a thermoplastic having a surface with alow coefficient of friction is preferred. Accordingly, fluoropolymerbased thermoplastics such as FEP, PFA, THV may be applicable. A barrieraccording to this aspect may be an FEP/ePTFE laminate obtained byfollowing the process taught in WO 94/13469 to Bacino. The barrier maybe formed at process temperatures above the softening temperature oreven above the melt of the FEP film in a female cavity mold.

The composite barrier of ePTFE and FEP described may allow forming ofsurprisingly thin, strong barrier films. In this embodiment, the ePTFElayer may act as a support during shape forming to allow thin barrierfilms. The porous ePTFE layer may also act as a reinforcement to thethermoplastic layer to maintain film strength and integrity of thebarrier layer as described above, the ePTFE porous layer can also serveas a bonding layer when a portion of the ePTFE is allowed to remainporous and oriented toward the inside of the mold.

Subsequent combination of a composite film with an elastomer through,for example, compression molding can allow the porous portion of theePTFE to be adhered to by partial penetration of the elastomer into theporous structure. Alternatively, if the ePTFE/FEP composite barrier isfully imbibed in a manner that leaves no residual porosity in thecomposite film, the composite barrier film can be chemically modified byetching or plasma or physically modified by roughening, for example, toallow bonding to the elastomer. In another aspect, the ePTFE porouslayer can be comprised of multiple layers of ePTFE, each having varyingpore size and structure. This multi layer construction may facilitatecontrol of the degree imbibing of the barrier polymer or the elastomeror to allow other desired properties.

One surprising element of some embodiments of the current invention isthat the porous film portion of the expanded fluoropolymer layer canmaintain its structure through thermoforming and post injection orcompression molding of the elastomer. This allows for some of theadvantages described above including improved compliance and sealabilityas well as improved bond between the barrier film and the elastomerbody.

In another embodiment, composite barrier is made by laminating a ePTFEporous layer to a densified ePTFE barrier layer using a thin layer of anadhesive, for example, a fluoropolymer thermoplastic like PFA. In thisembodiment, a syringe stopper of the current invention can be made bycombining composite barrier with an elastomer layer such that thethermoplastic bonds the densified ePTFE barrier layer and the porousePTFE layer. The ePTFE porous layer of the composite barrier is bondedto the elastomer i.e. stopper material during the molding process.

A composite film could be made by starting with a multilayer porousexpanded fluoropolymer film and substantially densifying one or more ofthe porous layers. In an aspect, the porous layer may be densified byapplication of pressure during the molding or syringe insertion process.

In another aspect, a porous expanded fluoropolymer film could be formed,then post applied to create a barrier layer. In one embodiment, thiscould be done by choosing an ePTFE film of suitable deformationcharacteristics that it allows for deformation into the mold atrelatively low temperatures (less than 200° C.). Such a suitable ePTFEfilm might, for instance, have tensile properties demonstrating highelongation, or low modulus at the deformation temperature. The ePTFEfilm can be formed into the female mold cavity through a variety ofmeans including through the use of air pressure, through the use of amale mold form, or other suitable means to allow forming of the ePTFE.One method would be to form such an ePTFE film during the injection orcompression molding process. This would allow for a structure whereinthe ePTFE comprised the outermost layer of the syringe stopper. The porestructure, thickness, and other properties can be suitably tailored toallow controlled penetration of the elastomer into the expandedfluoropolymer layer. In one embodiment, the elastomer is allowed topenetrate through the expanded fluoropolymer film, allowing for acomposite structure of expanded fluoropolymer film and elastomer at theouter surface. If the outer surface is suitably dense and nodal, it canallow for significantly reduce friction relative to the elastomeritself. A preferred embodiment utilizes a stopper created using theaforementioned process of forming an ePTFE film in a female mold, thenpost laminating, imbibing or coating a barrier onto the ePTFE'soutermost surface. In the coating and imbibing processes, the ePTFE canbe used to control the barrier thickness.

A syringe stopper of the current embodiment could be comprised of acomposite barrier comprised of multiple porous layers or multiplebarrier layers or both. The properties of a composite barrier soconstructed can be more suitably tailored to allow optimal compliancethrough the properties of the thin films while providing low surfacefriction against the barrel and adequate barrier properties toleachables, extractables and gas permeation.

Another means of making the ePTFE syringe stopper with porous outer andcreating a barrier layer would be to post densify the ePTFE withpressure and temperature.

It will be appreciated that there are many variations of the processesdescribed herein could be utilized without departing from the invention.Some of these variations may include, but are not limited to, thefollowing:

Any of the ePTFE fluoropolymers used in syringe stopper of the currentinvention could be made with an expanded fluoropolymer film based onPTFE, modified PTFE, and PTFE and TFE copolymers such as, for example,the resins as described in U.S. Pat. No. 6,541,589 and US Patentpublication 2009/0093602.

There are also a wide variety of processes for forming the film andattaching it to the elastomer body which may be utilized withoutdeparting from the invention. In addition to what is described above,one could form an ePTFE film at low temperatures.

In another aspect, the invention provides an improved tip cap for asyringe. A tip cap may be provided as a protective covering to a syringeneedle. Accordingly, a tip cap may provide a seal to the end of theneedle to prevent contamination of a medicament. As with a syringestopper, a tip cap construction that minimizes leachable and extractablecomponents is desirable. Moreover, the tip cap must be readilyremovable. Moderate friction between the tip cap and needle ispreferred. The tip cap according to the present invention therefore maybe of construction similar to that of the syringe stopper. In contrastto the stopper, however, the barrier layer is positioned in the tip capto be adjacent to the needle on final assembly. As the challengesbetween tip cap and stopper are similar, each of the constructionsdescribed herein with regard to stoppers may be adapted for use in a tipcap construction.

In another aspect, the invention provides an internal barrier layer fora container. The container may be of a material without barrierproperties. The addition of a barrier layer to the inside surface of thecontainer may improve barrier properties of the container. The containermay be made of any material, including thermoset material, thermoplasticmaterial, metal, ceramic or glass.

The container may be of a variety of materials. Advantageously, thecontainer is selected from materials that will form a bond with thebarrier layer. In one aspect, the container is advantageously formedfrom thermoplastic material. The container constructed of thermoplasticmay be formed separately or simultaneously with the barrier layer.Preferably, the barrier layer is pre formed to a shape approximating theinside of the container. The container and the preform may be placedtogether into a mold and formed under appropriate heat and pressure tothe final shape of the container with barrier layer. In this aspect thebarrier layer may form a strong bond with the thermoplastic of thecontainer during the final molding process.

In another aspect, the container may be a thermoset plastic. Thermosetplastics may be injected into the mold at the time of final molding ofthe barrier or barrier composite perform. In another aspect, thethermoset plastic may be formed or made by other means separately fromthe perform. In this aspect, the container of the thermoset plastic mayfunction as the mold, and the barrier layer or composite barrier layermaybe molded to the thermoset material.

The barrier may be selected from a number of combinations describedherein. In one aspect, the barrier is a composite of a densifiedexpanded fluoropolymer, such as ePTFE. The densified, expandedfluoropolymer may include copolymers of ePTFE. The densified expandedfluoropolymer may be combined with a thermoplastic such as FEP or EFEPto form a barrier composite.

During the molding process, additional layers may be added to thebarrier layer or composite barrier layer to construct a container or toimprove bonding of barrier or barrier composite to the container. Forexample thermoplastic layers may be added to improve bonding to athermoplastic container. In one embodiment PVDF sheet may be added tothe molding process. The PVDF layer may add some rigidity to athermoplastic container. In some embodiments, a relatively thickthermoplastic film may be formed in the mold to make the container. Inanother embodiment, a porous ePTFE film may be added between thethermoplastic layers to improve bonding between them.

The barriers and composite barriers of the present invention have shapesthat are uniquely high aspect. Various measures are known in the artwhich reflect the aspect of the molded part. Included among these areseveral common expressions of draw ratio, including areal draw ratio,linear draw ratio, and height to diameter ratio.

Each of these measures is understood to reflect the work put into athermoplastic during the molding process of simple shapes. From suchmeasures the relative difficulty of maintaining barrier integrity in themolding process can be inferred. While such measures are useful, they dohave limits in their ability to characterize complex shapes and tocompletely account for the thinning and breakdown of the barrierproperties of when molding such shapes.

In order to better account for complex molded shapes, the shape factormay be used. As used herein, the shape factor is a ratio of the majordiameter of the edge of a barrier to the maximum length of a crosssection perimeter of the barrier. The edge of the barrier is defined asthe intersection of an interior surface of the barrier and an exteriorsurface of the barrier. For example, for a syringe stopper, the barriermay be of generally convex shape. The interior surface of the barrier isoriented towards the glass syringe barrel and the exterior surfaceoriented towards the elastomeric material of the stopper. The barrieredge is the circular region at the intersection of the interior andexterior surface. The major diameter of the exemplary syringe istherefore the diameter of a circle defined by the barrier at the end ofthe stopper. The major diameter may also be understood to account forirregularly shaped barriers. The major diameter is considered thediameter the largest circle generally in plane with the barrier edgethat would contact some point on the edge. The maximum cross sectionlength is the longest length of the barrier perimeter in a cross sectionof the barrier made perpendicular to the major diameter.

In some constructions the shape factor may be conveniently determinedwith regard to measurements of the mold itself. In simple cylindricalshaped male and female molds for example, the major diameter may beapproximated by the mold diameter, and the maximum cross sectionperimeter length be calculated from the mold dimensions.

In other embodiments, the molded barrier may be of more complex shape.For example, a molded barrier may have a generally low aspect when theentire barrier is considered, but include features which are of highshape factor within the barrier or mold. In such embodiments, themaximum shape factor is best calculated with reference to the specificfeatures having shape factors. In such cases, the major diameter may beconsidered to be the major diameter of the feature and the cross sectionlength determined with reference to the feature and not the entirety ofthe molded barrier. For example, with reference to FIGS. 18A and 18B,the molded barrier 801 used in connection with a vial stopper 803. Thevial stopper has a insertion plug portion 804 and a flange portion 802.In this example, the major diameter of the barrier may be determinedwith reference to the insertion plug portion of the stopper rather thanthe larger diameter of the flange portion. The major diameter of theinsertion plug portion may be measured at the intersection 815 of theinsertion plug portion and the flange portion. Similarly, the maximumcross section length may ignore the flange of the stopper. Withreference to FIG. 18A, the maximum cross section is calculated as thesum of the perimeter length of each side 805 a and 805 b of the plug andthe perimeter length of the end of the plug 807. The perimeter length offlange portion 802 is not included in the calculation. In this manner,the forming challenge may be most properly considered by the shapefactor. The shape factor for several examples is tabulated below:

TABLE 1 Sample Example 9 Example 2 Example 10 Example 11 Major Diameter7.84 8.76 12.7 15.9 (mm) Cross Section 36.49 16.56 63.5 47.7 Length (mm)Shape Factor 4.7 1.9 5.0 3.0

Breaking and Sliding Friction Test

The following procedure was used to evaluate the static and dynamicfriction of embodiments of the invention. Each test syringe was attachedto a variable pressure pump (Barnant Air Cadet—model 420-3901) bysecuring a ¼″ OD, ⅛″ ID silicone tube to its tip (the tip was not fittedwith a needle). The stopper assembly with the barrier film waspositioned in the syringe to be at the bottom of its motion (closest tothe tip). At the beginning of each test, the pressure was slowlyadjusted starting at 2 psi and increasing about 1 psi every 30 secondsuntil syringe stopper movement was initiated (away from tip). Thepressure to initiate movement was noted as P break. After the movementwas initiated, the pressure was reduced to the lowest level that stillallowed sliding. This pressure was noted as P sliding. All pressureswere recorded in PSI. The test provided relative data on slidingproperties.

Air Leak Test

The same apparatus and setup as described above was then used toevaluate air leakage. The syringe stopper was attached to the pressurepump. However, in this test the stopper was moved to the topmostposition within the syringe (farthest from the tip) and the syringeassembly was placed in a 2 Liter glass beaker filled with deionizedwater. The pressure was set to 3 psi. If no leaks were detected (anysign of visual bubble formation) after 5 minutes, the pressure wasincreased by 1 psi. This procedure was repeated on each syringe untilleaking occurred (or about 15-17 psi when the air was sufficient toeject the syringe stopper from the barrel). The minimum pressurerequired to cause an observable leak after 5 minutes was recorded inpsi. This test was used for evaluating air leakage on Examples 1A, 1B,1C.

For Examples 1-8 and the comparative example, air leakage was evaluatedby performing the test as specified by I.S. EN ISO 7886-1:1998 Annex B,with the following exceptions: i) A bourdon tube gauge was used in placeof a manometer, and ii) Deionized water in place of freshly boiledwater.

Static and Dynamic Force Test

The test was performed as specified by I.S. EN ISO 7886-1:1998 Annex G,with the following exceptions: i) Syringe is mounted so that nozzle ispointing down, ii) No liquid was expelled; only air was expelled, andiii) Forces resulting form travel from the total graduated capacityposition to 20 mm from that point were recorded.

Static force is defined as the value at the first inflection point inthe force versus displacement graph. Dynamic force is the value after 15mm of travel.

Toluene Exposure Test

This test was used to assess the barrier properties of stoppers. Aschematic illustration of the test apparatus is shown in FIG. 14. Theinitial weight of the stopper was measured using a balance. The stopper(160) was loaded into the barrel (162) of a glass syringe. 1 ml ofToluene (166) was introduced into the barrel through the luer port(164). The luer port was sealed using a tip cap. The entire apparatuswas left under the lab hood for 5 hours at room temperature. After 5hours, the Toluene was removed from the barrel using a syringe. Thestopper was removed from the barrel using compressed air. Upon removalof the stopper, it was quickly dried using a Kimwipe® and immediatelyweighed using the balance. Lower the weight gain of the stopper comparedto its initial weight, the more effective its function as a barrier.Less than 1 mg weight gain of the stopper may indicate an effectivebarrier.

Vent Tube Installation Procedure

FIG. 15 describes a schematic of the test apparatus comprising a venttube (170) meant for a 1 mL standard stopper (as specified inISO11040-5) and a plunger (172). The vent tube, part of a SVH200Semiautomatic Stoppering Machine from Groninger was used in thisprocedure. The apparatus was loaded into a universal testing machinecapable of moving the plunger at a rate of 0.7 meters/sec. As shown inFIG. 15, the stopper (174) was placed on to the top of the vent tube(170). The test was initiated by moving the plunger at a rate of 0.7meters/sec to push the stopper through the vent tube. The test wascomplete when the stopper traversed the entire length of the vent tube.

Tensile, Modulus, Strain to Break

Materials were evaluated for tensile strength, modulus and strain tobreak according to ATM D882-10 using 0.25 inch by 3 inch samples and across head rate of 20 inches/min and one inch gauge length.

EXAMPLES Example 1A, 1B and 1C

Examples of certain embodiments of the invention were constructed usinga single layer of densified ePTFE films as the barrier. The films wereobtained by process described in U.S. Pat. No. 7,521,010 to Kennedy, etal. The films had thicknesses of 25 microns, 10 microns, and 5 microns,respectively. Eight commonly available disposable plastic syringebarrels and stoppers with shafts were obtained. Four were 1 ml plasticsyringes and four were 3 ml plastic syringes. Each included an elastomerstopper comprising a butyl rubber. The syringes were thoroughly washedwith 95% hexane to remove any silicone oil. The washed syringe barrelsand stoppers were allowed to dry for 5 days on an airhood to ensurecomplete evaporation of the hexane. Syringe stoppers were made by takinga densified ePTFE film and applying it to the stopper. Samples were madeusing these different film thicknesses. The films were first heated by aheat gun (Karl Leister, CH 6056—Hotwind S) set at 600° C. at a distanceof about 6-8 inches from the nozzle. The films were then drawn aroundthe stopper in the presence of the heat (thereby using the stopper as amale plug or mold). Care was taken to ensure that the film wasadequately heated so that it would readily form without distorting thestopper shape and the heat of the heat gun did not deform the stopper.The four densified ePTFE wrapped stoppers were installed into thesilicone free plastic syringe barrels for subsequent testing.

The table below demonstrates the performance as measured by the breakingand sliding friction test and the air leak test of each wrapped stoppercompared to a silicone oil control. It can be seen that the thindensified ePTFE films showed better performance than the relativelythicker films with respect to providing an airtight seal. This was inpart due to unavoidable wrinkling around the stopper contours in thisprocess.

TABLE 2 P break, P slide, P, min air leak Syringe Type Film Cover (psi)(psi) (psi) (1 mL) Example 1A 14 psi 12 psi 1 psi 1 mil Densified EPTFEExample 1B 14 psi 13 psi 10 psi 0.4 mil Densified EPTFE Example 1C 9 psi8 psi 13-15 psi 0.2 mil Densified EPTFE None/Silicone 7 psi 6 psi 16-18psi Oil BD (3 mL) Example 1A 8 psi 6 psi 1 psi 1 mil Densified EPTFEExample 1B 5-6 psi 3 psi 1 psi 0.4 mil Densified EPTFE Example 1C 5 psi3-4 psi 7 psi 0.2 mil Densified EPTFE None/Silicone 4-5 psi 2-3 psi >20psi Oil

Other embodiments of the present invention were constructed using aprocess of thermoforming a barrier preform and molding an elastomermaterial within the form to construct a syringe stopper.

Example 2

A barrier was created from a single densified ePTFE film 1.7-1.8 milthick, which was obtained by the process described in U.S. Pat. No.7,521,010 to Kennedy, et al. The film (104) was placed in thethermoforming equipment as depicted in FIG. 1 using the mold depicted inFIGS. 2A and 2B. The thermoforming equipment (100) uses hot air to heatthe mold (200), and the pressure drop through the apparatus supplies theforce to form the material. The mold has round cavities (202 a-d) havingdifferent dimensions. One of 0.380 inches, one of 0.372 inches, one of0.365 inches, and one of 0.358 inches. The bottom portion of thecavities have a rounded corner (203) with a radius of 0.079 inches, aside straight wall 205 of 0.188 inch height, and contain a 0.201 inchwide, 2 micron porous stainless steel disc (204) at its bottom mostpoint.

At room temperature a pressure of 5 psi was applied. The heater on thehot air system (102) (Osram Sylvania 6000 W, 240V, 25 A) was activatedusing a setpoint of 385° C. as measured by the thermocouple (106) abovethe mold. Once a temperature of 360° C. was reached below the moldcavities, as measured by the bottom thermocouple (108), the system washeld for 5 minutes. Pressure was then increased by increasing the inletair flow using the hot air system inlet valve (110). The pressure wasincreased at a rate of approximately 3 psi/minute from 5 psi to 13 psi.Above 13 psi, the pressure was increased at approximately 1 psi/minuteup to 18 psi. This pressure was sufficient to form the densified ePTFEsheet. The sample was held at this pressure for 5 minutes, and then theheater was deactivated allowing the mold and film to cool. The mold wasallowed to cool to below 50° C., as measured by the bottom thermocouple,before removing the sample. Any technique suitable for heating both thematerial and the mold as well as adding the air pressure to form thematerial will suffice. For example the mold may be simply boltedtogether and placed in an oven or heated press with an air line tosupply the pressure. Other processes known for thermoforming, bladderforming or vacuum forming may also be used.

To coat the inside of the barrier with an elastomer solution, samplecavities were filled with a 10% by weight solution of the elastomer inMEK and allowed enough time to dry so that a substantial amount of thesolvent was evaporated. Each cavity was loaded with 1-1.5 grams ofelastomer (Viton GF-600S from DuPont compounded with varox D8PH and Diak7 and processed to a crumb (304) by Eagle Elastomer Inc., CuyahogaFalls, Ohio). The mold (306) along with the above thermoformed densifiedePTFE sheet was loaded into a press with both platens (300, 302)preheated to 100° C. As represented in FIG. 3, a 10 mil Aluminum sheet(312) was placed on the lower platen (302). A Kapton sheet (308) and asteel caul plate (310) were placed below the upper press platen (300) toprovide uniform pressure. The sample was heated under no pressure for 45minutes, and then compressed under a force of 8000 lbs. The platens wereslowly closed and temperature based set points were used in thefollowing press cycle:

Step 1: Close platens

Step 2: Heat for 10 minutes at 100° C.

Step 3: 5 minutes at 120° C.

Step 4: 15 minutes at 175° C.

Step 5: 1 minute at 30° C.

Step 6: Open platens

Samples were then cut from the release sheet using a razor blade,affixed to a stopper rod using an acrylic adhesive (3M Scotch-WeldStructural Adhesive DP-8005) and installed within a standard 1 cc glasssyringe barrel free of silicone oil, and tested.

Example 3

A sample was prepared in a manner similar to Example 2 except that thedensified ePTFE barrier was formed to shape using a faster pressure ramprate. The procedure of Example 2 was followed except that a pressureramp rate of approximately 3 psi/minute from 5 psi to 18 psi was chosen.This ramp rate was obtained by closing only the exit air valve (112).This molding procedure resulted in a barrier film with milky appearance,which may indicate that there was some porosity induced in the materialby the speed of the forming process.

The mold cavity was then filled with elastomer, molded and attached to asyringe stopper according to the process described in Example 2. Afterinsertion into a glass syringe barrel the sample was tested.

Example 4

A sample was prepared in a manner similar to that described in Example2, except that one surface of the densified ePTFE barrier material wastextured before it was thermoformed. One side of the densified ePTFEmaterial was deformed using a coarse glass bead sandblaster. Thesandblaster nozzle was set to 15 psi and held approximately 9 inchesaway from the sample, which was affixed to a cardboard backer. Thesandblaster was passed 5 times over the entire surface of the sample.This process resulted in significant mechanical deformation on one sideof the film which increased the apparent surface roughness.

The barrier material was placed in the mold with the roughened side upso that it would be oriented towards the elastomer. The mold cavity wasthen filled with elastomer, molded and attached to a syringe stopperaccording to the process described in Example 2. After insertion into aglass syringe barrel, the sample was tested.

Example 5

A sample was prepared similar to Example 1 except that the densifiedePTFE barrier material exposed to a plasma treatment afterthermoforming. The material was left in the mold and placed in a plasmavacuum chamber with a 90/10 mix of He/H₂ and an exposure time of 10minutes. This sample was not coated with an elastomer solution beforecompression molding. Otherwise the procedures of Example 2 werefollowed.

The mold cavity was then filled with elastomer, molded and attached to asyringe stopper.

Example 6

A sample was prepared in a manner similar to Example 2, except that anePTFE/PFA composite film was used as a barrier. The barrier was obtainedin a manner similar to that described in Example 2 of WO 94/13469 toBacino. The resulting barrier is an ePTFE material with PFA on one ofits side surfaces. The barrier material was placed in the mold with thePFA side of the composite facing upwards, such that after thermoformingthe PFA would be oriented towards the inside of the mold. Thethermoforming process followed that of Example 2 except that the heatersetpoint was 295° C. and the mold cavity setpoint was approximately 275°C. Moreover, the pressure ramp rate in the molding process wasapproximately 11.5 psi/min from 5 to 18 psi. The composite material washeld at 18 psi for approximately 15 seconds before cooling. After thesample was removed from the mold it was inverted so that the ePTFE layerwas facing inward.

Example 7

A sample was prepared in a manner similar to Example 2 except that thebarrier was an ePTFE/densified ePTFE composite. The barrier was preparedaccording to the methods disclosed in U.S. Pat. No. 6,030,694 to Dolan.The material was oriented in the mold with the ePTFE side of thecomposite downward, the molded sample was inverted after thermoformingso that the ePTFE layer was facing inward. In this example the mold thatwas used had the same mold cavities of diameters identical to those ofExample 2 (“A”=0.380 inches, “B”=0.372 inches, “C”=0.365 inches,“D”=0.358 inches.) However, each cavity was a straight cylinder of 0.252inch height and had a stainless steel porous disc making up the bottomof the cavity.

Example 8

Another example was constructed using an ePTFE/FEP composite obtainedusing the procedure described in Bacino. In this example, rather thanthermoforming, the film was placed over a mold cavity and formed bycompression molding. A single cavity mold was used having a profiledepicted in FIG. 4. The mold had a primary diameter of 0.49 inches. Thebarrier material was obtained using the procedure described in Bacino.

Example 9

A layer of FEP about 0.5 mils in thickness (FEP 100, DuPont) waslaminated to a layer of densified expanded PTFE film [Thickness—1 mil;Tensile Strength—13.85 ksi (longitudinal), 13.9 ksi (transverse);Modulus—19.8 ksi (longitudinal), 20.7 ksi (transverse); Strain toBreak—425% (longitudinal), 425% (transverse)]. The two layers werestacked on top of each other in a pin frame and heating to 380° C. in anoven for 15 minutes. A layer of porous expanded PTFE [thickness: 27.5micrometers, matrix tensile strength: 66.8 MPa (longitudinal), 75.8 MPa(transverse), strain to break: 131% (longitudinal), 91% (transverse),bubble point: 22.6 psi] was placed on the densified ePTFE-FEP laminatesuch that the porous expanded PTFE layer faced the FEP layer in thelaminate. These three layers were placed between two smooth metalplates, the plates were clamped to a clamping pressure of about 1 psi.The plates were then placed in an oven at 305° C. for 15 minutes. Theresulting three layer composite material (densified ePTFE-FEP-porousePTFE) was then cooled to about 40° C.

This composite material was then thermoformed using heat and vacuum tocreate a pre-form. The pre-form was constructed by heating the compositeto a sufficiently high temperature and then drawing the composite over amale plug using differential pressure. The composite material was loadedinto the thermoforming apparatus such that the densified ePTFE layerfaced the plug. The composite was heated using a hot air gun (SteinelHG2310) with air exit temperature of 380° C. by placing the gun about 5mm away from the surface of the composite. After 5 seconds, the film wassubjected to a vacuum of −85 kPa. The composite was continued to beheated for another 15 seconds and cooled to about 40° C. under vacuum.

The resulting pre-form sample was then inverted and then placed into arubber molding cavity charged with 3.5 grams of elastomer (50 Durometerhalobutyl rubber), and the stopper was formed by compression molding.The mold was built to geometry specified for 1 mL standard plunger perthe ISO standard ISO11040-5:2001(E), with an additional 5% shrinkagefactor incorporated.

The cavity was loaded in a press with both platens preheated to 120° C.The platens were closed to 55,500 lbs (about 8700 psi total internalpressure). The platens were then heated at 180° C. for 5 minutes andthen cooled under pressure to 40° C. The pressure was released and thestopper was ejected. The resulting stopper was washed using a detergentand triple rinsed with de-ionized water. Stopper samples were then cutfrom the release sheet using a razor blade. They were subjected to two30 minute cycles in an autoclave at 121° C. The static and dynamic forceon the stopper was measured to be 2.5N and 2.1N respectively. The weightgain of the stopper after the Toluene Exposure test was 0 mg, indicatingthat the stopper functioned as an effective barrier. Further, the samestopper was subjected to the vent tube placement test and then theToluene exposure test was repeated. The weight gain was still 0 mg,indicative of superior barrier function of the stopper. The stopper wasalso tested for leaks using the air leak test and no leak was detected.The areal transformation (%) was calculated to be 82%.

Example 10

A layer of EFEP about 2.7 microns thick (RP-4020, Daikin) was laminatedto a layer of densified expanded PTFE film in a manner similar to theone described below. The densified expanded PTFE film had the followingproperties: Thickness—1 mil; Tensile Strength—13.85 ksi (longitudinal),13.9 ksi (transverse); Modulus—19.8 ksi (longitudinal), 20.7 ksi(transverse); Strain to Break—425% (longitudinal), 425% (transverse).The two layers were stacked on top of each other in a pin frame andheated to 380° C. in an oven for 15 minutes. The resulting two-layercomposite barrier (EFEP-densified expanded PTFE) was then cooled toabout 40° C.

This composite barrier was then thermoformed using heat and vacuum tocreate a pre-form. The pre-form was constructed by heating the compositeto a sufficiently high temperature to draw the composite over a maleplug using differential pressure. The mold consisted of a flat platewith a 60 mm diameter woven fiberglass mat placed over an opening in thecenter which had a 4.8 mm recess. The male plug was a 12.7 mm diameterpin 25.4 mm in height, and was placed in the center of the mold.

The composite barrier was loaded into the thermoforming apparatus suchthat the densified ePTFE layer faced the plug. The composite barrier washeated using a hot air gun (Steinel HG2310) with air exit temperature of380° C. by placing the gun about 5 mm from the surface of the compositebarrier. After heating for 5 seconds, the film was subjected to a vacuumof −85 kPa. The composite barrier was heated for another 15 seconds andcooled to about 40° C. while under vacuum.

An aluminum female mold which had a cavity of a geometry to match thethermoforming pin was prepared by heating to 280° C. The mold cavitymatched the geometry of the plug with 1.6 mm clearance on all sides.EFEP (RP-4020, from Daikin) resin was provided to the mold. Thethermoforming pin, with the pre-form on it, was also heated to 205° C.and inserted into the mold cavity. The entire assembly was cooled to 25°C. After cooling, the molded assembly was removed, providing a containerwith a wall thickness of approximately 1.6 mm and a PTFE based barrieron the interior of the container. The areal transformation (%) wascalculated to be 68%.

Example 11

Reference is made to FIGS. 17A and 17B in the following example. A layerof FEP (900) about 0.5 mils in thickness (FEP 100, DuPont) was laminatedto a layer of densified expanded PTFE (920) in a manner similar to theone described below. The densified expanded PTFE film had the followingproperties: Thickness—1 mil; Tensile Strength—13.85 ksi (longitudinal),13.9 ksi (transverse); Modulus—19.8 ksi (longitudinal), 20.7 ksi(transverse); Strain to Break—425% (longitudinal), 425% (transverse).The two layers were stacked on top of each other in a pin frame andheated to 380° C. in an oven for 15 minutes.

Next, a layer of porous expanded PTFE (940) was placed on the densifiedePTFE-FEP laminate such that the porous expanded PTFE layer faced theFEP layer in the laminate. The porous expanded PTFE membrane had thefollowing properties: Thickness—27.5 micrometers; Matrix TensileStrength—66.8 MPa (longitudinal), 75.8 MPa (transverse); Strain toBreak—131% (longitudinal), 91% (transverse); Bubble Point—22.6 psi.These three layers were placed between two smooth metal plates, theplates were clamped to a clamping pressure of about 1 psi. The plateswere then placed in an oven at 305° C. for 15 minutes. The resultingthree-layer composite material was then cooled to about 40° C.

The three-layer composite material (shown in FIG. 17A) was thenthermoformed in combination with an additional layer (960) of 10 milthick Kynar® 2800 PVDF, hand laid in contact with the porous ePTFE sideof the composite. Heat and vacuum were used to create a pre-form. Thepre-form was constructed by heating the composite to a sufficiently hightemperature to draw the composite over a male plug mold usingdifferential pressure. The three-layer composite material with theadditional PVDF layer was loaded into the thermoforming apparatus suchthat the densified ePTFE (920) layer faced the plug. The mold consistedof a 60 mm sintered stainless steel plate with a 8.3 mm lip on the outeredge and the plug located in the center. The plug was made of stainlesssteel and had a diameter of 15.9 mm and a height of 15.9 mm.

The composite with the additional PVDF layer was heated using a hot airgun (Steinel HG2310) with air exit temperature of 380° C. by placing thegun about 5 mm away from the surface of the composite. After heating for5 seconds, the film was subjected to a vacuum of −85 kPa. The compositewith the additional PVDF layer was heated for another 15 seconds andcooled to about 40° C. while under vacuum.

The resulting article (980) was shaped in the form of a container andshown in FIG. 17B. The areal transformation (%) was calculated to be118%.

Comparative Example A—Commercial Siliconized Butyl Stopper Made for 1 ccSingle Dose Glass Prefilled Syringe

TABLE 3 Static Dynamic Leak Force Force pressure Sample Material Cavity(grams) (grams) (kPa) Example 2 Densified A 1517.2 1232.7 Pass ePTFE C583.5 558.1 Pass D 358.4 287.1 −88 Example 3 Low porosity A 1528.41511.2 Pass ePTFE B 915.3 880.9 Pass C 621.8 735.6 Pass D 418.6 418.5−88 Example 4 Mechanically A 979.7 777.5 Pass deformed B 734.1 612.3Pass densified C 705.5 655.5 Pass ePTFE D 665.9 478.6 Pass B 1769.21635.4 Pass C 844.0 638.5 Pass D 574.6 415.3 −88 Example 6 ePTFE/PFA A2683.8 1991.0 Pass composite B 2244.4 1790.8 Pass C 1675.3 1291.0 PassComparative Butyl + n/a 750.5 323.7 Pass Example A silicone oil

1.-41. (canceled)
 42. A syringe stopper comprising: an elastomeric body;and an expanded polymer positioned on said elastomeric body.
 43. Thesyringe stopper of claim 42, wherein said expanded polymer is anexpanded fluoropolymer.
 44. The syringe stopper of claim 43, whereinsaid expanded fluoropolymer is expanded polytetrafluoroethylene.
 45. Thesyringe stopper of claim 43, wherein said expanded fluoropolymer isdensified expanded polytetrafluoroethylene.
 46. The syringe stopper ofclaim 43, wherein said expanded fluoropolymer has a thickness from 0.5microns to 20 microns.
 47. The syringe stopper of claim 42, wherein saidelastomeric body is comprised of a rubber constructed of butyl,bromobutyl, chlorobutyl, silicone, nitrile, styrene butadiene,polychloroprene, ethylene propylene diene, fluoroelastomers and blendsthereof.
 48. The syringe stopper of claim 42, wherein said densifiedexpanded fluoropolymer is pre-treated with at least one treatmentselected from chemical etching, plasma treating, corona, and physicalmodification.
 49. The syringe stopper of claim 42, wherein saiddensified expanded fluoropolymer is post-treated with at least onetreatment selected from chemical etching, plasma treating, corona,physical modification.
 50. The syringe stopper of claim 45, furthercomprising a plurality of barrier polymers positioned on said densifiedexpanded fluoropolymer.
 51. A syringe comprising the syringe stopper ofclaim
 42. 52. The syringe of claim 51, wherein said syringe is free oflubricant.